This paper reports on diagnostic and therapeutic management of pulmonary invasive fungal disease (IFD) in a child with relapsed acute myeloid leukaemia, undergoing chemotherapy followed by haematopoietic stem cell transplantation. Surgical management with resection of the involved lung tissue was based on the location of fungal infiltrates close to large circulatory vessels. After examination of resected pulmonary tissue, a diagnosis of proven IFD was done. This case report is an example that aspergillosis is usually the cause for pulmonary IFD. Pharmacotherapy of pulmonary IFD should be based on compounds with good penetration to lung tissue: amphotericin B lipid form or voriconazole.
Pneumonia is one of the most frequent cause of death after hematopoietic stem cell transplantation (HSCT). The objective of this review is to present various aspects of pneumonia in this group of patients, with focus on invasive pulmonary aspergillosis and cytomegalovirus disease, being the most frequent etiological causes of pneumonia after HSCT. The review is aimed at practical approach to diagnostic and therapeutic management of pneumonia after HSCT with special attention to: definitions of infections and level of diagnosis of upper and lower respiratory tract infections, including issues specific for invasive fungal disease, pneumocystosis, cytomegalovirus disease, community acquired respiratory viral infections and bacterial pneumonia. Another topics analyzed in the review are: epidemiology and risk factors for development of infection and risk of death due to pneumonia; invasive and non-invasive diagnostics, including imaging and laboratory biomarkers; methods of pharmacological and environmental prophylaxis and specific targeted therapy of pneumonia after HSCT.
It is well established that the benefit of myeloablative ALLO-HSCT can be associated with a potential high risk of procedure-related toxicity. The objective of this report is the analysis of complications in a 17-year-old girl with AML previously treated for medulloblastoma and myelodysplastic syndrome. Thiotepa, fludarabine, treosulfan and thymoglobuline were used in conditioning regimen. During conditioning neurological complications have occurred. MRI and CT scan results revealed the coexistence of PRES with the left internal carotid artery thrombosis. The effect of fludarabine on endothelial cells could possibly contribute to irreversible CNS damage and death in presented case.
Children with acute leukemia are at a high risk of invasive fungal disease, which might manifest itself as clinically-resistant entity. The objective of this paper is to present an unusual clinical case of 17-year-old patient treated for acute lymphoblastic leukemia, with early development of disseminated invasive aspergillosis, involving the abdominal, pulmonary and cardiac structures. The patient was subjected to a combined targeted double, and later triple, antifungal therapy together with several debulking surgical interventions. The clinical course indicated a highly clinically-resistant invasive fungal disease, and the treatment was unsuccessful in this case. Limited current experience in triple antifungal therapy, abdominal aspergillosis, Aspergillus endocarditis, and possible causes of failure of antifungal therapy are discussed in the paper.
In vitro antileukemic activity of five glucocorticoids and their cross-resistance pattern in childhood acute lymphoblastic and non-lymphoblastic leukemia were determined by means of the MTT assay in 25 leukemia cell samples of childhood acute leukemias. The equivalent antileukemic concentrations of the drugs tested were: 34 μM hydrocortisone (HC), 8 μM prednisolone (PRE), 1.5 μM methylprednisolone (MPR), 0.44 μM dexamethasone (DX) and 0.22 μM betamethasone (BET). In comparison with initial ALL cell samples, the relapsed ALL group was more resistant to PRE (38-fold, p = 0.044), DX (> 34-fold, p = 0.04), MPR (38-fold), BET (45-fold) and HC (33-fold). The AML cell samples were even more resistant to: PRE (>85-fold, p=0.001), DX (> 34-fold, p = 0.004), MPR (> 69-fold, p = 0.036), BET (> 69-fold, p = 0.038) and HC (54-fold, p = 0.059) when compared with ALL on initial diagnosis. A significant cross-resistance among all the glucocorticoids used was found. Only in some individual cases the cross-resistance was less pronounced.
Uptake and efflux of two anthracyclines, idarubicin (IDA) and daunorubicin (DNR), was studied in childhood acute leukemia samples. A comparison of IDA and DNR transport phenomena in relation to drug cytotoxicity and expression of P-glycoprotein (PGP) was made. Intracellular content of IDA/DNR was determined by flow cytometry using the fluorescent properties of the drugs. In vitro drug cytotoxicity was measured by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay. PGP expression was analysed by flow cytometry. The uptake and efflux rates were non-significantly higher for IDA than DNR. There were no differences between three types of leukemia with respect to drug content during accumulation and retention. After correction for the cell volume, intracellular concentration of both drugs in each moment of uptake and efflux was significantly lower in relapsed ALL and AML samples in comparison with initial ALL cells. Efflux, but not uptake, of both drugs was inversely correlated with PGP expression and IDA, but not DNR, cytotoxicity. The cytotoxicity was correlated with drug accumulation for both drugs and with drug retention for IDA. In conclusion, it seems that (1) intracellular content was related to the lipophilic properties of the drugs rather than to the type of leukemia, (2) decreased intracellular concentration of both drugs might have an impact on compromised therapy results in AML and relapsed ALL children, (3) IDA presents higher cytotoxicity, which possibly might be decreased by the presence of PGP. These results might have a practical impact on the rational design of new chemotherapy protocols.
Glufosfamide (β-D-glucosyl-ifosfamide mustard) is a new agent for cancer chemotherapy. Its pharmacology is similar to commonly used oxazaphosphorines, but it does not require activation by hepatic cytochrome P-450 and preclinically demonstrates lower nephrotoxicity and myelosuppression than ifosfamide. The aim of the study was a comparison of the drug resistance profiles of glufosfamide and other oxazaphosphorines in childhood acute leukemias. Leukemic cells, taken from children with ALL on diagnosis (n = 41), ALL on relapse (n = 12) and AML on diagnosis (n= 13) were analyzed by means of the MTT assay. The following drugs were tested: glufosfamide (GLU), 4-HOO-ifosfamide (IFO), 4-HOO-cyclophosphamide (CYC) and mafosfamide cyclohexylamine salt (MAF). In the group of initial ALL samples median cytotoxicity values for GLU, IFO, CYC and MAF were 15.5, 33.8, 15.7 and 7.8 μM, respectively. In comparison with initial ALL samples, the relative resistance for GLU and IFO in relapsed ALL samples was 1.9 (p = 0.049) and 1.3 (ns), and in initial AML samples 31 (p < 0.001) and 5 (p = 0.001), respectively. All oxazaphosphorines presented highly significant cross-resistance. Glufosfamide presented high activity against lymphoblasts both on diagnosis and on relapse.
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